非甾体类盐皮质激素受体(MR)拮抗剂在治疗高血压及其并发症方面具有广泛的临床应用价值。我们课题组从海洋红树林植物中分离得到了首个天然非甾体类MR拮抗剂-苯并大环内酯化合物-(3R)-去-O-甲基毛狄泼老素(DH-1)。它能够显著拮抗MR配体结合域与其共激活因子SRC1的结合活性并显著拮抗MR的转录活性,且具有较好的受体选择性，可作为抗高血压药物的先导化合物。本课题组前期对DH-1进行了结构修饰，发现了一些活性和选择性均优于DH-1的类似物，但前期构效关系研究不深入，化合物的MR拮抗活、选择性及水溶性方面均有待提高。基于此，本申请课题以MR为靶点，结合前期构效关系研究、药物化学及计算机辅助药物设计化学，对DH-1与MR活性位点的键合模型进行分析，合理设计、合成能与MR特异性结合的新型探针分子。通过活性评价，研究构效关系以及主要药效团，为定向设计高效、低副作用的非甾体类抗高血压药提供理论指导。

Non-steroidal antagonists of mineralocorticoid receptor（MR） have extensive clinically value in the treatment of hypertension and its complication. (R)-de-O-methyllasiodiplodin（DH-1）， a benzomacrolide isolated from marine magrove plant, was the first naturally occured non-steroidal MR antagonist. DH-1 showed significant antagonistic activity against the binding between MR-LBD(ligand binding domain) and nuclear receptor coactivator-SRC1(steroid receptor coactivator-1), and aganist the reverse transcription of MR， suggesting it having high selectivity agaisnt MR versus other steroid hormone receptors. The results indicated DH-1 could act as lead compound for the treatment of hypertension. In our previous studies, a few DH-1 analogs with stronger activity and higher selectivity was found，however,the structure-activity relationship （SAR） study is not sufficient, and the antigonistic activity, selevtivity and water-solubility still need to be improved urgently. Hence, based on preliminary SAR studies, pharmaceutical chemistry，and computer-aided drug design chemistry to analyze of binding model of MR and DH-1, in this project, novel probe molecules with specific binding to MR are reasonably designed, synthesized, and evaluated for MR antagonistic activity. The valuable study of SAR and pharmacophore could provide new theoretical guidance for designing effective non-steroidal anti-hypertension drugs with less side effects.